Invasive cancer cells are known to exhibit altered mechanosensation and mechanical properties during tissue invasion. Despite this, the extent to which mechanosensation and membrane biophysical properties contribute to the invasiveness of glioblastoma multiforme (GBM), one of the most lethal and treatment-resistant cancers, remains poorly defined. Emerging studies and preliminary findings indicate that the lipid metabolism and the plasma membrane lipid composition of GBM are modified, leading probably to changes in biophysical and mechanical properties of both plasma membrane monolayers and hence altered mechanosensation. For this reason, we characterized biophysical properties of individual plasma membranes monolayers in static and migrating GBM cells via fluorescence lifetime imaging of leaflet-selective polarity sensitive probes and anisotropy imaging of fluorescent lipids. We further used membrane modulators to selectively alter biophysical properties of the plasma membrane and study their impact on GBM invasiveness. Generally, it was revealed that outer plasma membrane monolayer packing was significantly increased in migrating cells compared to static ones and this effect was particularly pronounced at the leading edge of migrating cells. Interestingly, accessibility to plasma membrane cholesterol to methyl-β-cyclodextrin (MβCD) varied upon GBM cell lines, which correlated well with its ability to modulate membrane packing. Further, compositional modulation of the outer plasma membrane monolayer by the sphingomyelin phosphodiesterase inhibitor fluoxetine decreased membrane packing of the outer plasma membrane monolayer in all GBM cell lines. Both agents showed the ability to reduce GBM invasiveness and further experiments will establish the probable link between asymmetric membrane composition, monolayer packing, mechanical membrane properties, and mechanoreceptor signaling upon GBM invasion. All in all, this study will identify lipid-related therapeutic strategies and approaches to reduce invasiveness, showing the critical role of membrane lipid composition in cancer progression.
Kovryzhenko et al. (Sun,) studied this question.